Synthesis and Spectral Characterizationof 2-Substituted Indole Derivatives Subhi AI-Azawe and George Y. Sarkis' Department of Chemistry, College of Science, University of Baghdad, Baghdad, Adhamiya-Iraq
Twelve 2-substituted indole derivatives were synthesized by the Fischer indole method using polyphosphoric acid (PPA) as cyclodehydrating agent. Uv, ir, and nmr spectral data are reported. A number of general methods for the synthesis of indole derivatives have been reported (7). Among these, the well-known Fischer synthesis ( 7 , 2), proved to be the most versatile for the synthesis of indole compounds. In the present investigation, 2-substituted indole derivatives are prepared with good yields from phenylhydrazine and a series of methylketones, using polyphosphoric acid (PPA) as cyclodehydrating agent (3, 4, 6). It was found that the use of PPA gives indoles in good yields, which are about as high or higher than those reported ( 5 ) . I t has been found in this method that reaction time and temperature are critical factors (3, 4 ) . To determine the optimum temperature required for the cyclization of a given compound, a ,trace of the reactants is mixed with a few drops of PPA. If the mixture turns dark immediately, the reaction should be carried out in the cold; if the color changes gradually, room temperature is preferable; and if only a little color appears, heating is required. Most of the compounds synthesized gave light yellow or light red colors in the beginning, turning to bright red and finally deep red. The structure and physical properties of the synthesized indoles are given in Table I. Uv, ir, and nmr data for the synthesized 2-substituted indoles are given in Tables I I and I I I .. The ir absorption spectra of 2-substituted indoles showed an NH absorption at 3430-3140 cm-', due to
'
Present address, Department of Chemistry, McGill University, Montreal, Que., Canada. To whom correspondence should be addressed.
the free NH stretching vibration. Table I I shows marked variations in both frequency and intensity of this band in the indoles studied. Both were found to be very sensitive to the surrounding structure. The chemical shift and coupling constants in the nmr spectra of 2-substituted indoles are summarized in Table I I I. The assignments were as follows: In 5-indolinylindole (S), two triplets were observed at 3.2 and 4.1 6 (J = 7.5 Hz) for the two adjacent methylene groups. The triplet at 4 . 1 6 was assigned to the methylene group at position 2 next to the nitrogen, and the one at 3.2 6, to the methylene group at position 3 of the five-membered ring. These triplets are broad due to their coupling with the NH proton. The aromatic protons appeared as a complex pattern at 7.3, 7.5, and 7.8 6. The signals at 7.5 and 7.8 6 appeared as a group of partially resolved doublets and were assigned to the aromatic protons of the substituent indoline ring. Two other broad signals at 8.2 and 8.3 6, exchangeable with deuterium, were assigned to the two protons on the nitrogen atoms. The center of these bands was taken as the chemical shift of the corresponding proton. The olefinic proton appeared as a singlet at 7.25
6. The NH signal in compound 11, appeared as a doublet at 8.1 6, (J = 2.5 Hz), due to the coupling with the olefinic proton at C-3. On deuteration, this doublet disappeared and the doublet due to the proton at C-3 collapsed into a singlet, showing that long-range coupling does take place between the protons at positions 1 and 3 of the five-membered ring. Experimental Elemental analyses were performed by A . Bernhardt Laboratories, Ruhr, Germany. Melting points were taken
Table I. Characterization of 2-Substituted Indolesa
Molecular formula 1 2 3 4 5
6 7 8 9 10 11 12
R
MP, " C
Yield, %
Reaction temp, " C
Crystallization solvent
2-Naphthyl 2-Fluorenyl 4-Biphenyl 5- I ndanyl 3- I ndoiyi 5-lndolinyl 2-Pyridyi 3-Pyridyl 4-Pyridyl 2-Phenyl 2-p-Bromophenyl 2-p-N itrophenyl
163-164 180-1 82 167-169 127-129 190-191 173-174 153-1 54 133- 134 241-242 185-186 188-1 89
85 80 80 85 80 83 a5 80 82 75 80
100 110 110 130 110 120 120 135 130 100 110
Benzene Acetic acid Benzene Benzene Ethanol Ethanol Ethanol Ethanol Ethanol Benzene Benzene
132-133
77
130
Ethanol
-
Elemental analyses (C,H, N ) in agreement with theoretical values were obtatned and submitted for review
Journal of Chemical and Engineering Data, Vol. 18, No. 1, 1973 109
Table I I . Characteristic Ir and Uv Absorption of Substituted Indolesa
NH Stretch, cm-’
Aromatic or olefinic stretch, cm-’
1
3360m
3020w 3060w
2
3360m
3050w
Aliphatic
CH stretch, cm-l
2940m
C=C,
C=N, C-N stretch, cm-l
1605% 1510% 1440m, 1340m, 1260s 161Os,
1570% 1490% 1380m, 1300s, 1595s,
1500s, 1460m,
3
3330m
3020w 3040w
4
3380m
3020w 3060w 3080s
5
1430m, 1340m, 1260s 1670% 1570% 1480% 1420m, 1320% 2920s 2840s
3020w 3040w 3050w
6
3240m
3010w
7
3280m
3020w
8
3180m 3140m
3010w 3070w
9
3420m 3380m
3030w 3080m
10
3430m
3030m 3090w
11
3400m
3020w
12
3330m
1595m, 1540m, 1440m, 1400s, 1290m
1650% 1590% 1540s, 1490s, 1445% 1370% 1300s
1600% 1515s, 1430% 1375% 131Os 2940w
1400m, 1300m,
1570% 1485% 1410% 1320m,
1660% 1630s, 1590% 1480s, 1435% 1390% 1350m, 1320% 1250s 1600% 1570% 1550m, 1480s, 1440m, 1410s, 1370% 1330% 129Os, 1250s 1590% 1550% 1480% 1460% 1420s, 1350m, 1330m, 1280s 1625% 1540s, 1370m, 1280m 1600m, 1480% 1400m, 1300s
1590% 1470s, 1330w, 1520m, 1450m, 1350s,
1530m, 1470% 1 4 4 5 ~141 ~ 5% 1340% 1290s
1600% 1590s, 1540% 1490s, 1320s. 1250s
a s = strong, m = medium, w = weak.
110 Journal of Chemical and Engineering Data, Vol. 18,No. 1, 1973
CH
deformation, cm-’ 1 150% 960m, 9OOs, 830s, 700s 1240m, 1080m, 900m, 780% 750s, 1245% 1060s, 990m, 880m, 760s, 720s, 1235% 1150% 1040m, 965s, 855s, 705% 650s 1230% 1130% 1020% 930s, 800s, 670m, 1100m, 920w, 810m. 680m
A,,
m u loa e
1080m, 945m, 870s, 755s,
208(4.49) 235(4.63) 342(4.45)
1150m, 1 loom, 850m, 760% 700s 1140% 1000m, 950m, 835s, 745177, 680s 1170m, 1070m, 99Os, 880s, 750s, 680s,
209(3.55) 269(3.44) 350(3.35)
1170% 1100% 1000% 870m, 750s, 630m 1020m, 890w, 735m,
207(4.11) 229 (4.16) 290(3.81)
1150% 1080% 1030% 965% 890s, 810s, 750s, 700s, 620s 1240% 1 140% 1070m, 1040m, 99Os, 880m, 775s, 740% 685s 1230% 1190% 1160m, 1070s, 805% 750% 685s 1240m, 1220m, 1185m, 1070m, 1045m, 930m, 900m, 790s, 755s, 735m, 680s 1235m, 1180m, I l l o m , 1070s, lOOOs, 825s, 790% 745s, 700m, 650m 1185s, 1165% 880m, 850% 750s. 680s
210(4.35) 276(4.32)
206(4.00) 235(4.18) 288(3.45)
209 (4.02) 306(3.86) 347 (3.8 7)
206 (3.09) 255(2.89) 348(2.85)
207(4.13) 225(4.09) 300(3.94) 342(4.31) 206(4.00) 230(3.88) 330(4.22)
Table I l l . Nmr Data For 2-Substituted Indolesa
Solvent
1 2
3 4
5 6
CDC13 CDC13 CDCl3 CDC13 DMSO DMSO DMSO CDC13
7
DMSO
8
DMSO
9
DMSO CDC13
10 11
CDC13 DMSO
12
DMSO
O s
Aliphatic-H 8%ppm
Aromatic-H 6,ppm
3 . l t , 4.01t
7.55m, 7.9m, 8.22dd 7.3m, 7.85m, 8.05m 7.5m, 7.7s, 7.85s, 7.95s 6.78d, 6.9d, 7.3m, 7.38d 6.9m, 7.2m 7.0m, 7.4m, 7.8m 6.8m, 7.27m
3.2t, 4 . l t
7.3m. 7.5m, 7.8m
4 . 0 CH2 ~ ~ 2.0s, 2.08s 1.86% 1.9s
7.0m, 7.52s, 7.674, 8.3t, 8.42t, 8.73dd, 9.25d 7 . l m , 7.3d, 7.43d, 7.6% 7.854, 8.0d, 8.15d, 8.4m, 8.82dd 7.63m, 8.45d, 8.974 7.18d, 7.33d, 7.53m,8.lm, 8.58m 7.32m, 7.83m, 8.02m 7.2d, 7.324, 7.23m, 7.53m, 7.7m, 7.9d 7.0m, 7.3m,8.ld, 8.4d
7.255 7.285 7.22 5.7b5 7.05 7.015 6.955
J13
= 2.5
J23
=7
7.255
423
= 7.5
7.4d
J13
=2
9.77d
6.1b5
J13
=2
10.85b 9.08b
7.49bs 7.285
6.95b 8.ld
7.225 7.08d
9.85s
7.55
6.97b 7.50b
6.95 7.7bs 5.8b 8.05b 8.0b 7.68b 8.2b 8.3b 9.66s
= singlet, d = doublet, t = triplet, m = multiplet, b = broad, bs = broad singlet, JAB = coupling constant in AB systems.
on a Kofler melting point apparatus and are uncorrected. lr spectra were recorded on a Beckman I R 18A spectrometer. All compounds were examined in a potassium bromide matrix. Uv absorption spectra were obtained with a Unicam SP8OOB spectrophotometer on solutions in ethanol. Nmr spectra were measured on a Varian A60A spectrometer with tetramethylsilane (TMS) as the internal reference. Preparation of 2-Substituted Indoles A mixture of phenylhydrazine (0.01 mole) and the ketone (0.01 mole), were added to polyphosphoric acid (30 grams) in a flask protected from moisture. The viscous mass was mixed thoroughly and kept at the required temperature (Table I ) . The reaction mixture was stirred every few minutes and stopped as soon as a deep yel-
low, purple, or blue color was observed. The contents of the flask were poured into ice water (100 m l ) , and the product which separated was collected by filtration. Recrystallization of the crude product gave pure 2-substituted indole. Physical properties, yields, reaction conditions, and solvents of recrystallizations are given in Table I . Literature Cited (1) Fischer, E.,Jourdan, K., Eer., 16, 224 (1883). (2) Fischer, E.,Hess, R., ibid., 17, 559 (1884). (3) Homing, E. C., Koo, J., J. Amer. Chem. Soc., 73, 5826 (1951). (4) Kissman, H. M., Franswork, D. W., ibid., 74, 3948 (1952). (5) Shukri, J., AI-Azawe, S., J. lndian Chem. SOC..47, 2 (1970). (6) Snyder, H. R., Werber, F. X., J. Amer. Chem. Soc., 72, 2962 (1950). (7) Sumpton, W. C., Miller, F. M., "The Chemistry of Heterocyclic Compounds," p 606, Wiley, New York, N.Y., 1933. Received for review June 22, 1972. Accepted October 7, 1972. Research was supported by the University of Baghdad.
Journal of Chemical and Engineering Data, Vol. 18,No. 1, 1973 111
